Recovery of S100A8 in the absence of S100A9 exacerbates TNFα-mediated psoriatic-like arthritis (IRC4P.462)

Abstract

Abstract Psoriasis is a chronic autoimmune disorder and frequently associated with arthritis (PsA). Alarmins S100A8 and S100A9, expressed in granulocytes, monocytes and activated keratinocytes, are highly up-regulated in psoriatic skin and synovium. Although S100a8 mRNA remains unchanged in S100A9-deficient (S100A9-/-) mice, S100A8 protein expression is abrogated, thus generating a functionally double knockout mouse model. In general, S100A9-/- mice show reduced inflammatory activities in several mouse models of infection and inflammation. Recently, we generated ihTNFtgxS100A9-/- mice by crossing doxycycline-inducible human TNFα-transgenic mice (ihTNFtg) with S100A9-/- mice. Unexpectedly, we observed an enhanced disease progression in these mice as evidenced by increased loss of body weight, paw swelling and cartilage destruction and decreased grip strength compared to ihTNFtg mice upon TNFα induction. Interestingly, the enhanced disease progression was associated with re-expression of S100A8 protein upon TNFα induction, observed in bone marrow, blood, skin and nail keratinocytes by IHC staining and optical imaging. We hypothesize that in the absence of its binding partner S100A9, constitutively active S100A8 homodimers aggravate TNFα-mediated psoriatic-like arthritis. Our data indicate a complex S100A8/S100A9 regulatory mechanism of an alarmin-driven inflammation.